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Infect Immun. 2019 Jul 23;87(8). pii: e00409-18. doi: 10.1128/IAI.00409-18. Print 2019 Aug.

Role of Toll-Like Receptor 5 (TLR5) in Experimental Melioidosis.

Author information

1
Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands e.birnie@amc.uva.nl w.j.wiersinga@amc.uva.nl.
2
Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
3
Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
4
Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
5
Department of Medical Microbiology and Infection Control, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands.
6
Department of Medicine, Division of Infectious Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Abstract

The Gram-negative intracellular pathogen Burkholderia pseudomallei is the causative agent of melioidosis, an important cause of sepsis in Southeast Asia. Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is essential for an appropriate immune response during pathogen invasion. In patients with melioidosis, TLR5 is the most abundantly expressed TLR, and a hypofunctional TLR5 variant has been associated with improved survival. Here, we studied the functional role of TLR5 and its ligand flagellin in experimental melioidosis. First, we observed differential TLR5 expression in the pulmonary and hepatic compartments upon infection with B. pseudomallei Next, we found that B. pseudomallei-challenged TLR5-deficient (Tlr5-/- ) mice were more susceptible to infection than wild-type (WT) mice, as demonstrated by higher systemic bacterial loads, increased organ injury, and impaired survival. Lung bacterial loads were not different between the two groups. The phenotype was flagellin independent; no difference in in vivo virulence was observed for the flagellin-lacking mutant MM36 compared to the wild-type B. pseudomallei strain 1026b. Tlr5-/- mice showed a similar impaired antibacterial defense when infected with MM36 or 1026b. Ex vivo experiments showed that TLR5-deficient macrophages display markedly impaired phagocytosis of B. pseudomallei In conclusion, these data suggest that TLR5 deficiency has a detrimental flagellin-independent effect on the host response against pulmonary B. pseudomallei infection.

KEYWORDS:

Burkholderia pseudomallei ; TLR5; Toll-like receptor 5; flagellin; melioidosis; phagocytosis; sepsis

PMID:
31109950
PMCID:
PMC6652761
[Available on 2020-01-23]
DOI:
10.1128/IAI.00409-18

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